Pathophysiological regulation of the AT1-receptor and implications for vascular disease

Numerous studies have demonstrated that activation of the angiotensin II type 1 (AT1) receptor plays an important role in the pathogenesis of cardiovascular diseases.

AT1-receptor activation by angiotensin II is not only involved in the regulation of blood pressure, water and sodium homeostasis, and control of other neurohumoral systems, but also leads to excessive production of reactive oxygen species and to hypertrophy, proliferation, migration, and apoptosis of vascular cells. AT1-receptor-induced oxidative stress may cause nitric oxide inactivation, lipid oxidation, and activation of redox-sensitive genes, such as chemotaxis and adhesion molecules, pro-inflammatory cytokines, and matrix metalloproteinases, all of which are involved in the initiation and progression of endothelial dysfunction and manifested atherosclerosis. The expression levels of the AT1-receptor define the biological efficacy of angiotensin II. Many agonists, such as, for example, angiotensin II, growth factors, low-density lipoprotein cholesterol, insulin, glucose, estrogen, progesterone, reactive oxygen species, cytokines, nitric oxide, and many others, are known to regulate AT1-receptor expression in vascular cells. The pathophysiological relevance of dysregulated AT1-receptor expression has been demonstrated in many cell culture and animal studies and interventional trials in humans. Hypercholesterolemia, estrogen deficiency, and diabetes mellitus are associated with enhanced vascular AT1-receptor expression, increased oxidative stress, and endothelial dysfunction. Importantly, treatment with AT1-receptor blockers may inhibit the onset and progression of vascular oxidative stress and inflammation, endothelial dysfunction, atherosclerosis, and related organ damage.

Inhibition of AT1-receptor activation is presumably a primary treatment goal in patients suffering from cardiovascular risk factors or manifested atherosclerotic diseases.